Esters of acridan-10-carboxylic acid and methods for producing the same



Patented Dec. 23, i952 AND SAME METHODS FOR PRODUCING THE John W. Cusic, Skokie, IlL, assignor to G. D. Searle & 00., Chicago, 111., a corporation of- Illinois No Drawing. Application February 7, 1951,

' Serial N0. 209,917

18 Claims. (c1. 260 .2472) The present invention is concerned with a new type of ester of carbamic acid, wherein the nitrogen in the carbamic acid is a part of a cyclic radical, and more particularly with the estersof aJcridan lO-(zarboxylic' acid; 'such esters may be represented by the structural formula :In this structural formula, the radical R may be a lower alkyl radical or a substitution product thereof.

I have found that esters of particular medicinal interest are obtained where the R, radical is a basically substituted alkyl radical of-the type In this latter formula, alkylene represents such bivalent saturated aliphatic hydrocarbon radicals as ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, propylene, butylene, amylene, and hexalene, as well as more highly branched forms isomeric thereto. R and R" may represent such lower alkyl radicals as methyl, ethyl, propyl, butyl, amyl, and hexyl, wherein the propyl, butyl, amyl, and hexyl radicals may be either of the straight-chain, branched-chain, or cyclic type. The radical may also represent a nitrogen containing radical such as piperidirie, morpholine,

lupetidine, pyrrolidine,

like. 1

The organic bases of the foregoing type form ascorbic and related acids. They also form quaternary ammonium salts with a variety of orthiamorpholine, quinoline, isoquinoline, piperazine, N-alkylpiperazine and the 2 ganic esters of the sulfuric, hydrohaliaand aromatic sulfonic acids. Among such esters are methyl chloride and bromide, ethyl chloride, proi-r pyl chloride, butyl chloride, isobutyl,,chloride, benzylchlorideand bromide, phenethyl bromida naphthylmethyl chloride, dimethyl sulfate, ell;- ethyl sulfate, methyl benzene sulfonate, ethyl toluene sulfonate, ethylene chlorohydrin, propylene chlorohydrin, allyl bromide, methallyl bromide and crotyl bromide.

The object of this invention is to provide novelesters of acridan-lO-carboxylic acid. Certain of. these esters are valuable intermediates in organic. synthesis. Some of them, and particularly the basically substituted alkyl derivatives, have been found to possess a number of highly useful pharmacodynamic properties. These have a'profound effect upon the cardiovascular system, producing vasodilation. Quaternary ammonium derivatives have been found to inhibit the transmission of nerve impulses through the autonomic nervous system. Certain others of these esters are valuable as active ingredients in parasiticidal compositions of matter.

In one of the preferred methods for the pre'paration of these acridan-IO-carboXylates, acridan is heated with an ester of chloroformic acid and I 0 o -A.lkylene-Halogen This ester can then be converted to a basic deriv ative of the type discussed herein above by treat-1 ment with a suitable amine. An alternative approach to such ester, utilizes the reaction prod-. uct of acridan and phosgene, i. e. acridan-IO- carboxylic acid chloride, which is treated with a suitable alcohol to form esters in the usual way.

My invention will be described more fully in' It" should be understood, however, that these examples are given by way of illustration only and.- that thelinvention is not to be construed as limited in spirit or in scope by the details set conjunction with the following examples.

forth. It will be apparent to those skilled in the art that many modifications in materials and methods may be made without departing from the invention. In each of these examples, temperatures are given uncorrected in degrees centigrade C.), and quantities of material as parts by weight.

EXAMPLE 1 p-C'hloroefltyl ester of. acridan-IO-carboxylz'cccid A mixture of 905 parts of acridan and 715 parts of the chloroform-ate of p-chloroethanol in 8700 parts of anhydrous toluene is heated at refluxing temperature 01310 hours. After cooling, the reaction mixture is stirred with charcoal and filtered. The clear filtrate is evaporated and the greenish solid residue is recrystallized from ethanol. The chloroethyl' ester of acridan-lO-carboxylic acid melts at about 106- 108 C.

EXAMPLE 2 e-Dimethylaminoethyl ester of acridansm cdrboxylic acid 286 parts of the chloroethyl ester of vacridan- 10-.carboxylic acid are heated with 200 parts of dimethyl amine, 800 parts of butanone, and 10 parts of potassium iodide in a shielded pressure reactor at 65" C. for four days. The excess. of amine and the solvent are removed by heating on the steam bath. Upon addition of a mixture of dilute hydrochloric acid and ether, a yellow crystalline hydrochloride precipitates which is collected on a filter. The hydrochlorideof the fiedimethylaminoethyl ester of acridan-l-carboxylic acid melts at about 204-205 C.v .:It has thestructural formula fl-Diethylaminoethyl ester of acrz'dan-iO-carbozylic acid v330 parts of chloroethyl ester of acridan-locarboxylic acid are heated with 250 parts of diethyl amine and 880 parts of benzene-in a shielded pressure vessel at 80 C. for four days.

After evaporation of most of the solvent, the residue is treated with hydrochloric acid, ether, and benzene. The acid layer is separated, rendered alkaline by addition of dilute sodium hydroxide, and extracted with a mixture of ether and benzene. The extract isdried over anhydrous potassium carbonate, filtered, and evaporated. The-product consisting of an oily base remains.

EXAMPLE 4 Acridan-lfl-cdrboxylate of diethyZmethyl-(fi-hydram/ethyl) ammonium bromide 70 parts of p-dimethylaminoethyl ester of acridan-lO-carboxylic acid are reacted with 87.5 parts of methyl bromide in 400 partsv of butanone in a shielded pressure vessel. A solid precipitate forms within a few minutes. The acridanilfl -carboxylate. of diethylmethyl-(B-hydroxyethyl) -.ammonium bromide thus formed melts at about 220-221 C. with decomposition. The product has the structural formula ooo-cm-om-N-mn.

Br OH:

EXAMPLE 5 eB-Dimethyl-y-diisopropylaminopropyl ester of acridan-I O-cdrboazylz'c acid .360 parts .offlacridan are heated at refluxing temperature with 480 parts of -bromo-ep-dimethylpropyl chloroformate in 5000 parts of anhydrous toluene for twelve hours. The solution is filtered using charcoal as a clarifying agent.

Upon distillation of the solvent, the pLB-dimethyl-y-bromopropyl ester of acridan-lO-carboxylic acid is obtained. 500 parts of this ester are heated with 300 parts of diisopropylamine, 1O partsof potassium iodide and 2000 partsof butanone in a shielded reactor at 65 C..f0r five days. The excess of amine and of solvent are removed by heating on a steam bath. Dilute hydrochloric acid, ether and benzene are added to the residue and the acidic layer is separated and rendered alkaline by addition of dilute sodium hydroxide. The base thus obtained is extracted with ether. The ether extract is dried over anhydrous potassium carbonate, stirred with charcoal, and filtered. Upon filtration, the flfi-dimethyl-y-diisopropylaminopropyl ester of acridan-lO-carboxylic acid is obtained in the form of colorless crystals. It has the formula N on, CH(CHI)I J30 O-GHr--CHi-N .Ha omen),

EXAMPLE 6 N --(5 hydroxyethyl N methylaminoethanol :ester of .aCTidQn-IUr'CGTDOfCUZiC acid 2 parts of the chloroethyl ester of acridan- -carboxylic acid are heated at refluxing temperature with 225 parts of N-methylaminoetha- 1101, 10 parts of potassium iodide and 1600 parts of butanone. Most of the solvent is then distilled off and a mixture of dilute hydrochloric acid, ether and benzene is added. The acid layer is separated and rendered alkaline with ammonium hydroxide. An oil separates. The N-(B-hydroxyethyl) -N-methylaminoethanol ester of acridanlo-carboxylic acid is extracted with a mixture of ether and benzene. The extract is dried over anhydrous potassium carbonate, filtered and evaporated.

The hydrochloride is obtained by treatment of a solution of the base in a mixture of benzene and ether with alcoholic hydrogen chloride. The resulting precipitate is separated and recrystallized from isopropanol. The hydrochloride thus obtained melts at about 174-175 c 115 a structural formula r I EXAMPLE 7 B-Morpholinoethyl ester of acridan-iO-carboflllic acid 286 parts of the chloroethyl ester of acridan- IO-carboxylic acid are heated with 200 parts of morpholine, 10 parts of potassium iodide and 1600 parts of butanone for ten hours at the refluxing temperature. The reaction mixture is concentrated on the steam bath. Addition of dilute hydrochloric acid to the residue yields a solid precipitate which is filtered off. The filtrate is rendered alkaline whereupon the fl-morpholinoethyl ester of acridan-lO-carboxylic acid precipitates. The latter is collected on a filter and washed with water. It is recrystallized from ethanol using charcoal as a clarifying agent. The crystals melt at about 124-125 C.

I claim:

1. Esters of acridan-lO-carboxylic acid of the class consisting of lower alkyl, lower haloalkyl and lower basically substituted alkyl esters.

2. Basically substituted esters of acridan-IO- carboxylic acid of the structural formula wherein R is a basically substituted lower alkyl radical.

3. The lower dialkylaminoalkyl esters of acridan-lO-carboxylic acid oi. the structural formula formula Alkyl 5. Acridan-lO-carboxylates of. lower hydroxy- 6. a1kl,lami'nonium' salts for the. structural Iomula v s I wherein X is one equivalent of an anion.

6. Acridan-lO-carboxylates of lower fi-hydroxyethyltrialkylammonium salts of the structural formula N Alkyl I 3/ C O O-GHr-CHz- A1ky1 X" Alkyl I I wherein X is one equivalent of an anion.

7. The lower heterocyclylalkyl esters of acridan-lO-carboxylic acid of the structural formula halogen-alkylene-O-CO-halogen 9. The process of preparing chloroalkyl esters of acridan-lO-carboxylic acid which comprises heating acridan with chloroformyl ester of a chlorinated alcohol of the type Cl-alkylene-O-CO-Cl in an inert organic solvent in which both reactants are soluble.

10. The process of preparing compounds defined as in claim 2, which comprises reacting acridan with the haloformyl ester of a halogenated alcohol of the type halogen-alkyleneO-CO-halogen and reacting the resulting haloalkyl ester of acridan-lO-carboxylic acid with the corresponding amine.

11. The dimethylaminoethyl ester of acridan- 10-carboxylic acid.

12. The acridan-lO-carboxylates of diethylmethyMB-hydroxyethyl)ammonium halides of the structural formula wherein X is a halide ion.

7 :1-3. The fi-morphclincethyl-ester or acridan- IO-carboxylic acid.

14. The lower hydroxyalkylalkylaminoalkyl esters of acridan-lO-carboxylic acid of the structural formula N /R 0. O-Alkylene-N wherein R is a lower alkyl and R is a lower hydroxyalkyl radical.

15. The lower N-(B-hydroxyethyl)-N-alkylaminoethyl esters of acridan-lQ-carboxylic acid of the structural formula REFERENCES CITED The following references are of record in the file of this patent:

UNITED STATES PATENTS Name Date Semon Aug. 22, v1939 OTHER REFERENCES Burtner et a1., Chem. Abstracts, vol. 37, p. 5719 (1943).

Number 

1. ESTERS OF ACRIDAN-10-CARBOXYLIC ACID OF THE CLASS CONSISTING OF LOWER ALKYL, LOWER HALOALKYL AND LOWER BASICALLY SUBSTITUTED ALKYL ESTERS. 